Cholesterol and copper are crucial to nutrition and normal brain function but recent evidence also implicates both in Alzheimer's disease. Cholesterol is important for cell structure, repair and signaling, hormone production and bile acid synthesis but is also a major risk factor for atherosclerosis, coronary heart disease, and Alzheimer's disease. A high-cholesterol diet can result in beta amyloid deposits - a hallmark of Alzheimer's disease. Copper is important for growth, cardiovascular, endocrine and pulmonary function but copper imbalance has been linked to mental retardation, anemia, toxicosis and Alzheimer's disease. Copper is involved in beta amyloid metabolism, aggregation, toxicity, appears to be elevated in the blood of Alzheimer's patients, and is one of the trace metals found in senile plaques of post-mortem Alzheimer's brains. We have established that cholesterol and copper affect classical conditioning of the rabbit nictitating membrane response and heart rate. New data suggest cholesterol can retard the recall of "old" memories - those formed before a high cholesterol diet. The hypothesis on which the current renewal is based is that cholesterol and beta amyloid affect learning and memory and that the mechanism involved is mediated by direct and indirect effects of cholesterol on the CNS. The current proposal tests this hypothesis with three specific aims will focus on cellular and molecular mechanisms underlying cholesterol effects on acquisition of new memories (Specific Aim 1) and investigate the effects of cholesterol on memory retention (Specific Aim 2). Once we understand the effects of cholesterol on retention we will then examine its cellular and molecular mechanisms (Specific Aim 3). This work is important because of the impact it will have on understanding the role of dietary cholesterol and beta amyloid deposits in learning and memory and on our understanding of the pathogenesis of failures in learning and memory. The research will be of considerable significance because it will establish a clear role for cholesterol, copper and beta amyloid in learning and memory and advance the field by adding the cholesterol-fed rabbit as a valuable non-transgenic tool to the search for treatments of and a cure for Alzheimer's disease. The proposed work is innovative because it combines classical conditioning of the rabbit NMR - a well- understood behavioral and neural model of learning and memory - with the simple dietary manipulation of feeding cholesterol to examine the effects of cholesterol and beta amyloid - two of the "smoking guns" of Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Cholesterol is a major risk factor for cardiovascular disease and there is now evidence that cholesterol is a major risk factor for Alzheimer's disease. Consequently, high cholesterol appears to be the major factor in two of the most widespread diseases in the US. The cholesterol-fed rabbit has been the primary model for cardiovascular disease for 90 years and has recently been shown to accumulate beta amyloid in the brain. Thus, feeding a rabbit cholesterol would make a good non-transgenic model of Alzheimer's disease. Moreover, reducing cholesterol levels may be as viable a means of reducing beta amyloid accumulation as it is in treating heart disease.